Use of amino acids for treatment of various conditions

ABSTRACT

A method of treating a patient for a condition characterized by symptoms that can be alleviated by interfering with or supplementing the activity of endogenous ligands on the a2S subunit of a voltage gated calcium channel, said method comprising: administering to a patient experiencing the condition an amount of one or more of L-norleucine, L-isoleucine, L-alloisoleucine, L-methionine, Lleucine, 2-cyclohexylglycine, 2-phenylglycine, 2-amino-2-norbornane carboxylic acid, 1-aminocyclohexane carboxylic acid, 2-aminoheptanoic acid, 2-aminocaprylic acid, and 2-aminononanoic acid under conditions effective to treat the condition, wherein when the condition is a hot flash or a symptom of hormonal variation, the compound is not L-leucine.

This application claims the priority benefit of U.S. Provisional PatentApplication Ser. No. 60/395,975 filed Jul. 12, 2002, which is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates generally to the use of a therapeuticallyeffective amount of various compounds, or compositions containing suchcompounds, to treat conditions that are believed to be mediated by theα₂δ subunit of voltage gated calcium channels (“VGCC”).

BACKGROUND OF THE INVENTION

Gabapentin and various γ-amino-butyric acid (GABA) derivatives oranalogs have been reported to be useful for treating a number ofconditions. These include: hot flashes and symptoms of hormonalvariation (U.S. Pat. No. 6,310,098 to Guttuso, Jr.); seizures (U.S. Pat.No. 6,359,169 to Silverman et al.); vertigo and migraine headaches (U.S.Pat. No. 6,333,352 to Derakhshan); chronic pain disorders (U.S. Pat. No.6,316,638 to Bryans et al.); symptoms of neurodegenerative diseases suchas Parkinson's Disease, Alzheimer's Disease, Huntington's Disease,Multiple Sclerosis, Amyotrophic Lateral Sclerosis, etc. (U.S. Pat. No.6,359,169 to Silverman et al.); restless legs syndrome (U.S. Pat. No.6,316,638 to Bryans et al.); tremor disorders (Magnus, “NonepilepticUses of Gabapentin,” Epilepsia, 40:S66-S72 (1999)); nausea (U.S. Pat.No. 5,916,903 to Viner); anxiety and depression disorders and insomnia(U.S. Pat. No. 6,372,792 to Chouinard and U.S. Pat. No. 6,306,910 toMagnus et al.); various sleep disorders (U.S. Pat. No. 6,586,478 toAckman et al.); both irritable bowel syndrome and inflammatory bowelsyndrome (U.S. Pat. No. 6,242,488 to Bueno et al.) as well asgastrointestinal damage caused by drugs and alcohol (U.S. Pat. No.6,426,368 to Bueno et al.); obsessive compulsive disorders, generalizedanxiety disorders, and impulse control disorders, which may includegambling disorders, compulsive eating, body dysmorphic disorders,hypochondriasis, pathological grooming conditions, kleptomania,pyromania, and attention defecit hyperactivity disorder (U.S. Pat. No.6,462,084 to Dewey et al.); and drug addiction (U.S. Pat. No. 6,541,520to Dewey et al.).

Gabapentin and GABA derivatives or analogs have been shown to bind to asingle site in the brain with high affinity, the α₂δ subunit of VGCC(Bryans et al., “3-Substituted GABA Analogs with Central Nervous SystemActivity: A Review,” Med. Res. Rev. 19:149-177 (1999)). It is believedthat their interaction with this site is responsible for their clinicalefficacy for multiple indications such as those listed above.

Despite the success of gabapentin and GABA derivatives or analogs intreating numerous conditions, gabapentin use is associated with variousside effects, most often sleepiness and dizziness, leading to anapproximately 13 percent patient withdrawal rate (Backonja et al.,“Gabapentin for the Symptomatic Treatment of Painful Neuropathy inPatients with Diabetes Mellitus: A Randomized Controlled Trial,” JAMA280:1831-1836 (1998); Rowbotham et al., “Gabapentin for the Treatment ofPostherpetic Neuralgia: A Randomized Controlled Trial,” JAMA280:1837-1842 (1998)). Finally, as a prescription drug, use ofgabapentin is often too costly and poorly accessible for some patientswho are in need of an effective treatment for their condition(s). Itwould be desirable, therefore, to identify other compounds that are welltolerated and substantially free of side effects, less expensive thanexisting therapies, and readily accessible.

The present invention overcomes these and other deficiencies in the art.

SUMMARY OF THE INVENTION

The present invention relates to a method of treating a patient for acondition characterized by symptoms that can be alleviated byinterfering with or supplementing the activity of endogenous ligands onthe α₂δ subunit of a voltage gated calcium channel (“VGCC”), the methodincluding the step of administering to a patient experiencing thecondition an amount of one or more of L-norleucine, L-isoleucine,L-alloisoleucine, L-methionine, L-leucine, 2-cyclohexylglycine,2-phenylglycine, 2-amino-2-norbornane carboxylic acid,1-aminocyclohexane carboxylic acid, 2-aminoheptanoic acid,2-aminocaprylic acid, and 2-aminononanoic acid under conditionseffective to treat the condition, wherein when the condition is a hotflash or a symptom of hormonal variation, the compound is not L-leucine.

Another aspect of the present invention relates to a composition in asingle unit dosage form that includes: a pharmaceutically ororganoleptically acceptable carrier, and one or more compounds selectedfrom the group consisting of 2-cyclohexylglycine, 2-phenylglycine,2-amino-2-norbornane carboxylic acid, 1-aminocyclohexane carboxylicacid, 2-aminoheptanoic acid, 2-aminocaprylic acid, 2-aminononanoic acid,L-norleucine, L-isoleucine, L-alloisoleucine, L-methionine, andL-leucine, wherein the single unit dosage form includes an amount of theone or more compounds which is effective to treat a conditioncharacterized by symptoms that can be alleviated by interfering with theactivity of endogenous ligands on the α₂δ subunit of a voltage gatedcalcium channel.

The present invention affords effective treatment of a number ofconditions or disorders, whereby any number of the above-identifiedcompounds can be administered individually or in combination, eitheralone or in the form of a pharmaceutical composition or a nutritionsupplement, for purposes of treating the various conditions ordisorders. The compounds disclosed herein are believed to act on the α₂δsubunit of the VGCC, the site where gabapentin and GABA analogs andderivatives are believed to have their effect. However, unlikegabapentin and GABA analogs and derivatives, the compounds disclosedherein for use in accordance with the present invention are believed tobe well tolerated and (unless otherwise noted) substantially free ofside effects, less expensive, and readily accessible.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the treatment of various conditionsusing one or more of the following compounds: 2-cyclohexylglycine orH-cyclohexyl-Gly-OH (Bachem Bioscience, Inc., King of Prussia, Pa.),2-phenylglycine (Aldrich Chemical Company, Inc., Milwaukee, Wis.),2-amino-2-norbornane carboxylic acid (Sigma Chemical Co., St. Louis,Mo.), 1-aminocyclohexane carboxylic acid (Sigma Chemical Co.),2-aminoheptanoic acid (Sigma Chemical Co.), 2-aminocaprylic acid (SigmaChemical Co.), 2-aminononanoic acid (Sigma Chemical Co.), L-norleucine(Peptides International, Inc., Louisville, Ky.), L-isoleucine (PeptidesInternational, Inc.), L-alloisoleucine (Sigma Chemical Co.),L-methionine (Peptides International, Inc.), and L-leucine (PeptidesInternational, Inc.).

Each of the above-identified compounds is commercially available insubstantially pure form (e.g., 95% or higher) or, depending on thecompound, as a racemic mixture. Both the substantially pure compoundsand the compounds present as a racemic mixture are useful in accordancewith the present invention.

The compounds can be administered alone or as a component of acomposition in the form of a pharmaceutical or nutritional supplement

Of the above-listed compounds, L-norleucine, L-isoleucine, L-methionine,and L-leucine are naturally occurring amino acids and, therefore, can beadministered in the form of a nutritional supplement.

The remaining compounds, L-alloisoleucine, 2-cyclohexylglycine,2-phenylglycine, 2-amino-2-norbornane carboxylic acid,1-aminocyclohexane carboxylic acid, 2-aminoheptanoic acid,2-aminocaprylic acid, and 2-aminononanoic acid are non-naturallyoccurring compounds and, therefore, can be administered in the form of apharmaceutical.

Effective amounts of the compound(s) will depend upon the mode ofadministration, frequency of administration, and the type ofpharmaceutical or nutritional supplement composition used to deliver thecompound into a patient. Generally, effective amounts of such compoundswill be about 0.01 to about 300 mg/kg·body wt. per day, preferably about0.1 to about 200 mg/kg·body wt. per day, more preferably about 1 toabout 100 mg/kg·body wt. per day. Typical daily doses will be from about10 to about 5000 mg per day for an average adult patient of normalweight. While individual needs vary, determination of optimal ranges ofeffective amounts of each compound is within the abilities of those ofskill of the art.

The nutritional and/or pharmaceutical composition will include one ormore of the above-identified compounds in combination with a suitablecarrier. In the case of the pharmaceutical composition, the carrier is apharmaceutically acceptable carrier. In the case of a nutritionalsupplement, the carrier is an organoleptically suitable carrier.

For compositions of the present invention, it is preferable that suchcompositions are in the form of a single unit dosage form that containsan amount of the one or more compounds effective to treat the conditionto be alleviated.

Other compositions encompassed by the present invention include thosecontaining two or more of the above-identified compounds in combinationwith suitable carriers. The compositions of the present invention mayexclude other active ingredients or, alternatively, the compositions canbe administered in combination with other therapeutic regimen that areknown in the art, whether now known or hereafter developed.

The nutritional supplement and/or pharmaceutical composition can alsoinclude suitable excipients, or stabilizers, and can be in solid orliquid form such as, tablets, capsules, powders, solutions, suspensions,or emulsions. Typically, the composition will contain from about 0.01 to99 percent, preferably from about 5 to 95 percent of active compound(s),together with the carrier.

The one or more compound(s), when combined with a suitable carrier andany excipients or stabilizers, whether administered alone or in the formof a composition, can be administered orally, parenterally,subcutaneously, transdermally, intravenously, intramuscularly,intraperitoneally, by intranasal instillation, by implantation, byintracavitary or intravesical instillation, intraocularly,intraarterially, intralesionally, or by application to mucous membranes,such as, that of the nose, throat, and bronchial tubes (i.e.,inhalation).

For most therapeutic purposes, the one or more compound(s) can beadministered orally as a solid or as a solution or suspension in liquidform, via injection as a solution or suspension in liquid form, or viainhalation of a nebulized solution or suspension.

The solid unit dosage forms can be of a conventional type. The solidform can be a capsule, such as an ordinary gelatin type containing theone or more compound(s) and a carrier, for example, lubricants and inertfillers such as, lactose, sucrose, or cornstarch. In another embodiment,these compounds are tableted with conventional tablet bases such aslactose, sucrose, or cornstarch in combination with binders like acaciaor gelatin, disintegrating agents such as cornstarch, potato starch, oralginic acid, and a lubricant such as stearic acid or magnesiumstearate.

For injectable dosages, solutions or suspensions of the one or morecompound(s) can be prepared in a physiologically and pharmaceuticallyacceptable diluent as the carrier. Such carriers include sterileliquids, such as water and oils, with or without the addition of asurfactant and other pharmaceutically and physiologically acceptablecomponents, including adjuvants, excipients or stabilizers. Illustrativeoils are those of petroleum, animal, vegetable, or synthetic origin, forexample, peanut oil, soybean oil, or mineral oil. In general, water,saline, aqueous dextrose and related sugar solutions, and glycols, suchas propylene glycol or polyethylene glycol, are preferred liquidcarriers, particularly for injectable solutions.

For use as aerosols, the compound in solution or suspension may bepackaged in a pressurized aerosol container together with suitablepropellants, for example, hydrocarbon propellants like propane, butane,or isobutane with conventional adjuvants. The materials of the presentinvention also may be administered in a non-pressurized form such as ina nebulizer or atomizer.

With respect to the naturally occurring amino acids described above, apatient may alternatively increase administration of these compounds bymodifying his or her diet accordingly. Thus, by consuming foods that arehigh in these compounds, a patient may increase his or her daily intakeof these amino acids to produce a therapeutic effect with respect to thevarious indications listed above. Foods high in L-norleucine includevegetables, especially green leafy vegetables; foods high in L-leucineinclude eggs, fish, lentils, poultry, beef, seeds, soy, wheat, almonds,dairy, beans, and brown rice; and foods high in L-methionine includefish, eggs, dairy, beans, beef, garlic, onion, lentils, and soybeans.Because L-leucine is naturally converted by the body into L-isoleucineand L-norleucine, the above foods rich in L-leucine can increase the invivo concentration of L-isoleucine and L-norleucine.

Even though a patient may increase intake of these naturally occurringamino acids by diet, nutritional supplements and/or pharmaceuticalcompositions can also be administered in accordance with the presentinvention.

The various conditions that can be treated in accordance with thepresent invention are those conditions characterized by symptoms thatcan be alleviated by interfering with or supplementing the activity ofendogenous ligands on VGCC, particularly the α₂δ subunit of the VGCC.Without being bound by belief, regardless of the route and form ofadministration, it is believed that the above-listed compounds can beused to treat a variety of conditions by virtue of their bindingactivity on the α₂δ subunit of the VGCC.

The various conditions that can be treated in accordance with thepresent invention include, without limitation, hot flashes and symptomsof hormonal variation; seizures; vertigo and migraine headaches; chronicpain disorders; symptoms of neurodegenerative diseases including,without limitation, the symptoms of Parkinson's Disease, Alzheimer'sDisease, Huntington's Disease, Multiple Sclerosis, and AmyotrophicLateral Sclerosis; tic disorders; tremor disorders; nausea; cough;hiccups; asthma; hyperhidrosis; sleep disorders; fatigue; fibromyalgia;premature labor; preeclampsia and eclampsia; irritable bowel syndromeand inflammatory bowel disease; gastrointestinal damage caused by drugsand alcohol; drug addiction; obsessive compulsive disorders, generalizedanxiety disorders, and impulse control disorders; and attention defecithyperactivity disorder.

Thus, one aspect of the present invention relates to a method oftreating the above-listed conditions in a patient which is carried outby administering an amount of the one or more of the above-identifiedcompounds to a patient experiencing symptoms of one or more of theabove-listed conditions in a manner effective to treat those symptoms.Alternatively, an agent that is converted by the body into one of theabove-identified compounds can be administered to the patient. Bytreating a particular condition, the present invention encompasseseither reducing the number of symptomatic events, reducing the severityof symptomatic events, or both.

The patient to be treated is any mammalian patient, preferably a humanpatient, either female or male.

With respect to treatment of hot flashes and symptoms of hormonalvariation, it should be appreciated to those of skill in the art thatthe ultimate cause of hot flashes can, of course, be markedly differentfor male and female patients. For example, in female patients the hotflash is a primary symptom resulting from menopausal or postmenopausalhormonal variation. However, the hot flash can also be drug-induced byanti-estrogen compounds (e.g., tamoxifen, raloxifene, leuprolideacetate, etc.) or surgically-induced by removal of estrogen-producingtissues (e.g., total abdominal hysterectomy, bilateralsalpingo-oophorectomy, etc.). In male patients, the hot flashestypically occur as a side-effect of androgen-deprivation therapy formetastatic prostate cancer. They can be either surgically-induced (e.g.,bilateral orchiectomy) or drug-induced (e.g., treatment with agonadotrophin-releasing-hormone agonist, leuprolide acetate, etc.). Thepresent invention is directed to treatment of hot flashes and associatedsymptoms of hormonal variation that are affiliated with these and othercauses thereof.

Nausea and emesis (or vomiting) are often induced by stimulation ofeither the chemoreceptor trigger zone or the emesis center in thecentral nervous system. Such stimulation can be caused by afferentstimulation (e.g., tactile pharyngeal impulses, labrynthinedisturbances, motion, increased intracranial pressure, pain, distentionof viscera, or psychologic factors) or blood born emetic substances(e.g., as seen during pregnancy or during episodes of premenstrualsyndrome, cancer chemotherapy, uremia, radiation therapy, electrolyteand endocrine disturbances, or the presence of chemical emeticsubstances). Nausea and vomiting are also common post-operative sideeffects resulting from the use of anesthetics. The present invention isdirected to treatment of nausea and emesis that are affiliated withthese and other causes thereof.

Fatigue includes that associated with chemotherapy administration, withother medication therapy or toxin exposure, with a disease state, andthat occurring without known cause.

Chronic pain disorders can include both neuropathic and non-neuropathicpain disorders. Examples include, but are not limited to, diabeticneuropathy, post-herpetic neuralgia, trigeminal neuralgia, occipitalneuralgia, carpal tunnel syndrome, chronic headache conditions, chronicbackache conditions, arthritis, bursitis, tendonitis, muscle cramping,myositis, and myopathy conditions.

Sleep disorders can include, generally, both dyssomnias and parasomnias.Exemplary sleep disorders to be treated include, without limitation,insomnia, sleep apnea, REM sleep disorders, restless legs syndrome,periodic leg movements of sleep, and night terrors.

Tremor disorders include but are not limited to those associatedParkinson's Disease, Essential Tremor, Intention Tremor, Rubral Tremor,Orthostatic Tremor, Physiologic Tremor, Cerebellar Tremor, drug-inducedtremor, idiopathic tremor, cerebral ischemia, tardive dyskenesia,spasticity, and other disorders associated with dopaminergic neuronmalfunction. It has been demonstrated the GABA-ergic neurons projectonto dopaminergic neurons of the ventral tegmental area and areinhibitory in nature. Therefore, it is evident that modifying theactivity of GABAergic neurons may affect the activity of dopaminergicneurons and, hence, be useful to treat conditions in which thedopaminergic neurons are implicated.

Tic disorders include can include common simple motor tics such as eyeblinking, neck jerking, shoulder shrugging, facial grimacing, andcoughing, common simple vocal tics such as throat clearing, grunting,sniffing, snorting, barking, common complex motor tics such as facialgestures, grooming behaviors, jumping, touching, stamping, and smellingof objects; common complex vocal tics such as repeating words or phrasesout of context, coprolalia (use of socially unacceptable words,frequently obscene), palilalia (repeating one's own sounds or words),and echolalia (repeating the last heard sound, word, or phrase); andmultiple tic disorders such as Tourette's syndrome.

Symptoms of neurodegenerative diseases or disorders that can be treatedinclude bradykinesia, rigidity, tremors, postural instability,depression, and other symptoms associated with Parkinson's Disease;dementia and other symptoms associated with Alzheimer's Disease; choreadystonia, dementia, athetosis, and other symptoms associated withHuntington's Disease; spasticity, weakness, optic neuritis, and othersymptoms associated with Multiple Sclerosis; and muscle atrophy,fasciculation of muscles, spasticity, weakness, optic neuritis, andother symptoms associated with Amyotrophic Lateral Sclerosis.

Migraine is a disorder characterized by persistent headache, which maybe severe, which may be associated with visual and gastrointestinaldisturbances, and which may also be recurrent. The head pain associatedwith migraine may be unilateral or generalized. Migraine can recur at afrequency that varies widely, from daily events to once in severalmonths. An untreated acute migraine episode can endure for as long asmany hours or several days.

Cough can be a result of infection, drug-induced, secondary to asthma oremphysema, or idiopathic.

Hiccups can be drug-induced, surgically-induced, or idiopathic.

Hyperhidrosis can be drug-induced, surgically-induced (also known ascompensatory sweating), secondary to hormonal fluctuations, oridiopathic.

Irritable Bowel Syndrome is a functional bowel disorder in whichabdominal pain is associated with defecation or a change in bowelhabits. IBS has elements of an intestinal mobility disorder, a visceralsensation disorder, and a central nervous system disorder. While thesymptoms of IBS have a physiological basis, no clear mechanism unique toIBS has been identified. Rather, the same mechanisms that causeoccasional abdominal discomfort in healthy individuals seems to operateto produce the symptoms of IBS. Persons with IBS exhibithypersensitivity, particularly hyperalgesia, in response to painfuldistensions in the small bowel and colon and to normal intestinalfunction. There are also increased or unusual areas of visceral pain,often worsened by meals and alleviated upon defecation. Together, thegastrointestinal disorders of IBS and inflammatory bowel diseaseencompass a wide range of disease states, including without limitationCrohn's disease, ileitis, ischemic bowel disease, ulcerative colitis,dyspepsia, gastroesophogeal reflux for functional bowel disorders, andother forms of visceral pain.

Gastrointestinal damage caused by drugs and alcohol can be take the formof mild dyspepsia, gastritis, peptic ulcer disease, as well as moresevere gastrointestinal complications such as bleeding and perforation.It is well known that symptoms from drug and alcohol withdrawal caninclude, among others, tremors, anxiety, convulsions, hallucinations,and confusion.

Obsessive compulsive disorders, generalized anxiety disorders, andimpulse control disorders are characterized by obsessive and/orcompulsive behaviors. Obsessive behaviors typically include recurrentand persistent thoughts, impulses or images that occur over and overagain and feel out of an individual's control. Compulsive behaviorsinclude acts or compulsions that an individual performs over and overagain, often according to certain rules. Obsessive compulsive disordersinclude general anxiety disorder, pathological or compulsive gamblingdisorders, compulsive eating, body dysmorphic disorders,hypochondriasis, pathological grooming conditions, kleptomania,pyromania, attention deficit hyperactivity disorder, and other impulsecontrol disorders.

EXAMPLES

The following examples are provided to illustrate embodiments of thepresent invention but are by no means intended to limit its scope.

Example 1 Administration of L-Methionine to Patients Experiencing HotFlashes as Symptoms of Postmenopausal Hormone Variation

Patient No. 1

A 55 year old post-menopausal woman had experienced about 10 hot flashesper day for the past four years. After receiving gabapentin therapy forseveral days, she was unable to tolerate the drug due to severedizziness.

L-methionine 1 gram tid was administered orally. After three weeks, a 90percent improvement in hot flash frequency resulted. This benefitpersisted for the 3 months of therapy. No side effects were experiencedfrom L-methionine administration.

This patient had previously tried L-methionine at 500 mg three timesdaily for two weeks without noticing an appreciable change in hersymptoms.

Patent No. 2

A 57 year old post-menopausal woman had experienced about 15 hot flashesper day for the past two years. L-methionine 1 g tid was administeredorally and after three weeks of administration a 90 percent improvementin hot flash frequency resulted. This benefit persisted for the 5 monthsof therapy. No side effects were experienced from L-methionineadministration.

Patent No. 3

A 57 year old post-menopausal woman had experienced about 7 hot flashesper day for the past two years. L-methionine 500 mg tid was administeredorally. After three weeks of administration, a 66 percent improvement innighttime hot flash frequency resulted and a 50 percent improvement inboth nighttime and daytime hot flash severity resulted. No side effectswere experienced from L-methionine administration.

Despite the absence of side effects, all three patients were instructedto discontinue L-methionine when a literature review revealed thathigh-dose oral L-methionine can increase serum homocysteine levels by10-fold (van der Griend et al., Vasc. Med. 7:29-33 (2002), which ishereby incorporated by reference in its entirety). Since elevated serumhomocysteine is associated with increased risks for development ofcardiovascular disease, patients were told to discontinue L-methioninetherapy.

Even though a potential side effect exists for L-methionineadministration, the above examples demonstrate that L-methionineadministration can be used to treat hot flashes and other symptoms ofgonadal hormone variation resulting from menopause.

Example 2 Administration of L-Methionine to a Patient Experiencing HotFlashes as a Result of the Post-Partum State

A 36 year old woman had experienced 3 severe nighttime and 2 moderatedaytime hot flashes per day since giving birth to her first child 5years ago. Nighttime hot flashes have been accompanied with severesweating, requiring the patient to change her nighttime clothes threetimes a night. L-methionine 1 g bid was administered orally and afterthree weeks of administration, a 100 percent improvement in hot flashfrequency resulted. No side effects were experienced from L-methionineadministration.

Despite the absence of side effects, this patient was instructed todiscontinue L-methionine when a literature review revealed thathigh-dose oral L-methionine can increase serum homocysteine levels by10-fold (van der Griend et al., Vasc. Med. 7:29-33 (2002), which ishereby incorporated by reference in its entirety). Since elevated serumhomocysteine is associated with increased risks for development ofcardiovascular disease, this patient was told to discontinueL-methionine therapy.

Even though a potential side effect exists for L-methionineadministration, the above example demonstrates that L-methionineadministration can be used to treat hot flashes and other symptoms ofgonadal hormone variation resulting from postpartum state.

Example 3 Administration of L-Methionine to a Patient ExperiencingPalmar Hyperhidrosis

A 35 year old man with palmar hyperhidrosis for 20 years experienced a50% reduction in the subjective severity of his condition after 3 weeksof therapy with L-methionine 1 g bid administered orally. No sideeffects were experienced from L-methionine administration.

Despite the absence of side effects, this patient was instructed todiscontinue L-methionine when a literature review revealed thathigh-dose oral L-methionine can increase serum homocysteine levels by10-fold (van der Griend et al., Vasc. Med. 7:29-33 (2002), which ishereby incorporated by reference in its entirety). Since elevated serumhomocysteine is associated with increased risks for development ofcardiovascular disease, this patient was told to discontinueL-methionine therapy.

Even though a potential side effect exists for L-methionineadministration, the above example demonstrates that L-methionineadministration can be used to treat palmar hyperhidrosis.

Example 4 Administration of L-Norleucine to Patients Experiencing HotFlashes as Symptoms of Postmenopausal Hormone Variation

Patient No. 1

A 57 year old female with 6 hot flashes/day at baseline experienced a70% reduction in hot flashes starting 10 days after initiating oraltherapy with L-norleucine 1.5 grams, 2×/day. This level of efficacy wasmaintained for the 3.5 months of therapy. No side effects wereexperienced.

Patient No. 2

A 61 year old female with 8 hot flashes/day at baseline experienced an87% reduction in hot flashes starting 4 days after initiating oraltherapy with L-norleucine 1 gram, 2×/day. This level of efficacy wasmaintained for the 1.5 months of therapy. No side effects wereexperienced.

The above examples demonstrate that L-norleucine administration can beused to treat hot flashes and other symptoms of gonadal hormonevariation resulting from menopause.

Although the invention has been described in detail for the purposes ofillustration, it is understood that such detail is solely for thatpurpose, and variations can be made therein by those skilled in the artwithout departing from the spirit and scope of the invention which isdefined by the following claims.

1. A method of treating a patient for a condition characterized bysymptoms that can be alleviated by interfering with the activity ofendogenous ligands on the α₂δ subunit of a voltage gated calciumchannel, said method comprising: administering to a patient experiencingthe condition an amount of one or more of L-norleucine, L-isoleucine,L-alloisoleucine, L-methionine, L-leucine, 2-cyclohexylglycine,2-phenylglycine, 2-amino-2-norbornane carboxylic acid,1-aminocyclohexane carboxylic acid, 2-aminoheptanoic acid,2-aminocaprylic acid, and 2-aminononanoic acid under conditionseffective to treat the condition, wherein when the condition is a hotflash or a symptom of hormonal variation, the compound is not L-leucine.2. The method according to claim 1 wherein the compound is L-norleucine.3. The method according to claim 1 wherein the compound is L-isoleucine.4. The method according to claim 1 wherein the compound isL-alloisoleucine.
 5. The method according to claim 1 wherein thecompound is L-methionine.
 6. The method according to claim 1 wherein thecompound is L-leucine.
 7. The method according to claim 1 wherein thecompound is 2-cyclohexylglycine.
 8. The method according to claim 1wherein the compound is 2-phenylglycine.
 9. The method according toclaim 1 wherein the compound is 2-amino-2-norbornane carboxylic acid.10. The method according to claim 1 wherein the compound is1-aminocyclohexane carboxylic acid.
 11. The method according to claim 1wherein the compound is 2-aminoheptanoic acid.
 12. The method accordingto claim 1 wherein the compound is 2-aminocaprylic acid.
 13. The methodaccording to claim 1 wherein the compound is 2-aminononanoic acid. 14.The method according to claim 1 wherein compound is administered in anamount of about 10 to about 5000 mg per day.
 15. The method according toclaim 1 wherein said administering is carried out orally, parenterally,subcutaneously, transdermally, intravenously, intramuscularly,intraperitoneally, by intranasal instillation, by implantation, byintracavitary or intravesical instillation, intraocularly,intraarterially, intralesionally, or by application to mucous membranes.16. The method according to claim 1 wherein the compound is present in apharmaceutical composition comprising the compound and apharmaceutically-acceptable carrier.
 17. The method according to claim16 wherein the pharmaceutical composition is in a liquid or solid dosageform.
 18. The method according to claim 1 wherein the compound ispresent in a nutritional supplement comprising the compound and anorganoleptically suitable carrier.
 19. The method according to claim 18wherein the nutritional supplement is in a liquid or solid dosage form.20. The method according to claim 1 wherein the condition is one or moreof hot flashes or symptoms of hormonal variation, seizures, vertigo,migraine headaches, chronic pain disorders, a neurodegenerative disease,tic disorders, tremor disorders, nausea, cough, hiccups, asthma,hyperhidrosis, sleep disorders, fatigue, fibromyalgia, premature labor,preeclampsia or eclampsia, irritable bowel syndrome, inflammatory boweldisease, gastrointestinal damage caused by drugs and alcohol, drugaddiction, obsessive compulsive disorders, generalized anxietydisorders, impulse control disorders, and attention deficithyperactivity disorder. 21-46. (canceled)
 47. A composition in a singleunit dosage form comprising: a pharmaceutically or organolepticallyacceptable carrier and one or more compounds selected from the groupconsisting of 2-cyclohexylglycine, 2-phenylglycine, 2-amino-2-norbornanecarboxylic acid, 1-aminocyclohexane carboxylic acid, 2-aminoheptanoicacid, 2-aminocaprylic acid, 2-aminononanoic acid, L-norleucine,L-isoleucine, L-alloisoleucine, L-methionine, and L-leucine, wherein thesingle unit dosage form comprises an amount of the one or more compoundswhich is effective to treat a condition characterized by symptoms thatcan be alleviated by interfering with the activity of endogenous ligandson the α₂δ subunit of a voltage gated calcium channel.
 48. Thecomposition according to claim 47 wherein the composition comprises twoor more compounds.